Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

Laboratories must document successful analytic validation of all immunohistochemical tests before applying to patient specimens. The parameters for cases included in validation sets, including number, expression levels, fixative and processing methods, should take into account intended use and should be sufficient to ensure that the test accurately measures the analyte of interest in specimens tested in that laboratory. Recommendations are also provided for confirming assay performance when there are changes in test methods, reagents, or equipment.

Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Background Pleomorphic lobular carcinoma in situ (PLCIS) of the breast is a distinctive entity, and yet its behavior and management are unclear. The purpose of this study was to review a relatively large number of cases and to evaluate the risk of recurrence. Methods Cases of PLCIS (n=47) over a 12 year-period were reviewed. The clinical, radiologic and pathologic findings were recorded. Immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR) and HER2 were performed. Results Thirty-one patients had no concurrent or past history of breast cancer, six (19.4%) of which had local recurrence. All tumors (4 invasive carcinoma and two PLCIS) were ipsilateral. Younger age at presentation was a high risk factor for local recurrence with mean and range of 52.5 (44, 59) vs. 60.6 (40, 81) years (p=0.03). Three of 31 patients were treated with radiation therapy (RT), none of which developed local recurrence. PLCIS had an adverse ER/PR/HER2 molecular profile with at least 41.2% of the cases overexpressing HER2. Moreover, at least 11.7% of the cases were triple negative. Conclusions This study included the largest number of patients that had no past or concurrent history of breast cancer with the longest clinical follow-up, providing an insight to the management practices and risk of recurrence from PLCIS.